QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.103.061788v1 309/2/776    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Eisinger, D. A. Articles by Schulz, R. Search for Related Content PubMed PubMed Citation Articles by Eisinger, D. A. Articles by Schulz, R.

CELLULAR AND MOLECULAR

Extracellular Signal-Regulated Kinase/Mitogen-Activated Protein Kinases Block Internalization of -Opioid Receptors

Institute of Pharmacology, Toxicology and Pharmacy, University of Munich, Munich, Germany

Translocation of G protein-coupled receptors (GPCRs) from the cell membrane to cytosol depends on the kind of ligand activating the receptor. This principle is clearly demonstrated for opioid receptors, because diverse opiate agonists rapidly induce receptor internalization, whereas morphine almost fails. We report here the impact of mitogen-activated protein (MAP) kinase isoforms extracellular signal-regulated kinase (ERK)1/2 on the internalization of -opioid receptors (DORs) expressed in human embryonic kidney (HEK)293 cells. Receptor activation by etorphine turned out to transiently phosphorylate ERK/MAP kinases and bring about DOR internalization within 20 min. In contrast, prolonged exposure of HEK293 cells to morphine excited persistent phosphorylation of ERK/MAP kinases, and those cells failed to internalize the opioid receptor. When ERK/MAP kinase phosphorylation was blocked by 2'-Amino-3'-methoxyflavone (PD98059), morphine gained the ability to strongly induce DOR endocytosis. The importance of activated MAP kinases for DOR internalization is further demonstrated by glutamate and paclitaxel because these substances induce phosphorylation of ERK1/2 and concomitantly prevent DOR sequestration by etorphine. In addition, receptor internalization by morphine was facilitated by inhibition of protein kinase C and opioid-mediated transactivation of epidermal growth factor receptor (EGFR), both activating ERK/MAP kinases by opioids. The mechanism affording DOR internalization by PD98059 may relate to arrestin, which uncouples GPCRs and thus triggers receptor internalization. Arrestin considerably translocates toward the cell membrane upon DOR activation by morphine in presence of the MAP kinase blocker, but it fails in the absence of PD98059. We conclude that ERK/MAP kinase activity prevents opioid receptor desensitization and sequestration by blocking arrestin 2 interaction with activated DORs.

Address correspondence to: Dr. Daniela A. Eisinger, Institute of Pharmacology, Toxicology and Pharmacy, University of Munich, Koeniginstrasse 16, 80539 Munich, Germany. E-mail: eisinger{at}pharmtox.vetmed.uni-muenchen.de

This article has been cited by other articles:

				S. Gavi, D. Yin, E. Shumay, H.-y. Wang, and C. C. Malbon Insulin-Like Growth Factor-I Provokes Functional Antagonism and Internalization of {beta}1-Adrenergic Receptors Endocrinology, June 1, 2007; 148(6): 2653 - 2662. [Abstract] [Full Text] [PDF]